The application of immunohistochemistry (IHC) in diagnostic gastrointestinal (GI) pathology is similar to that in many other organ systems. The most commonly used markers are epithelial cell markers, such as cytokeratin AE1/3, cytokeratin 7, cytokeratin 20 and CDX-2, and markers for common mesenchymal tumors such as CD117, CD34, S100, and desmin, etc. Tumors of neuroendocrine origin are probably more commonly seen in the digestive and pulmonary systems. A synaptophysin and chromogranin immunostain generally can confirm their neuroendocrine nature. Use of IHC to evaluate dysplasia in Barrett’s esophagus is investigational, although many have found p53 overexpression helpful in confirming dysplasia, particularly in high-grade dysplasia. The use of IHC in nonneoplastic diseases of the GI tract is limited. A few new markers like GATA-3, PAX8 and SATB-2 were found helpful in differentiating certain metastases, such as lobular carcinoma of the breast, from primary GI tumors, including gastric signet ring cell carcinoma. Interpretation of IHC results needs to be in the right histopathologic context and proper clinical setting to avoid pitfalls. A few rare GI tract tumors described in recent years, including plexiform fibromyxoma of the stomach and GI neuroectodermal tumor (GNET), are worth mentioning. Finally, in conjuction with immunohistochemistry, molecular pathology will broaden its role in pathology practice as demonstrated by Her-2/neu amplification, CDH-1 and Kit gene mutation tests in upper GI tract tumors.